FULL PROJECT 1 - UNDERSTANDING AND TARGETING OF CONVERGENT IMMUNOSUPPRESSIVE PATHWAYS AND MOLECULAR SIGNALING IN HPV-POSITIVE AND HPV-NEGATIVE PENILE CANCER PROJECT SUMMARY/ABSTRACT Penile cancer (PeCa) is a highly morbid disease that exhibits a higher mortality among Puerto Ricans than among the rest of the US population. The theme of the U54 grant, Infection-Driven Malignancies Program for Advancing Careers and Translational Sciences (IMPACT), fits well with our project because infection with human papillomavirus (HPV) has been identified as a risk factor for penile cancer. The etiology of penile cancer is incompletely understood. Therefore, there is an urgent need to address knowledge gaps. We recently developed the first genetically engineered mouse (GEM) models of penile squamous cell carcinoma (PSCC), the predominant histologic type of PeCa, through co-deletion of tumor suppressor genes (Smad4, Apc) in mouse penile epithelium. We have also generated the first set of patient-derived xenograft (PDX) models for PeCa (N=6). In our pilot project, using this GEM model of PSCC, we found: (1) substantial infiltration of immune cells in the penile tumors, especially myeloid-derived suppressor cells (MDSCs) that can inhibit cytotoxic T cells and cause immune evasion, and (2) strong cyclooxygenase-2 (COX2) expression in penile tumors and PI3K/mTOR signaling in MDSCs. Further using expression arrays we identified novel insights into expression patterns associated with human HPV+ and HPV- PeCa.The objective of this proposal is to develop therapeutic strategies for PeCa and validate molecular pathways associated with HPV+ and HPV- PeCa subtypes. Our hypotheses are that (1) PeCa formation is promoted by chronic inflammation as a result of HPV infection or downregulation of essential tumor suppressor genes SMAD4 and APC, (2) The key signaling hubs driving PeCa progression, including COX2 and PD-L1 upregulation, are effective targets for immunotherapeutic intervention,and (3) Estrogen and Notch signaling are upregulated in HPV+ PeCa and play important roles in PeCa progression. The specific aims of this proposal are to: (Aim 1) Eradicate mouse penile cancer by combining targeted therapy and immunotherapy, (Aim 2) Identify the immunologic profiles associated with HPV infection in human penile cancer to optimize therapy, and (Aim 3) Validate and target both Estrogen and Notch signaling in HPV+ penile cancer. The proposed studies will have a significant impact on both the understanding of the molecular pathways that drive HPV+ and HPV- PeCa subtypes and the identification of effective therapeutic strategies to treat these highly morbid tumors. Through this unique collaboration our multidisciplinary research teams from The University of Texas MD Anderson Cancer Center and the University of Puerto Rico are poised make novel contributions to understanding and curing this rare fatal cancer.